Liquid Biopsy and Circulating Biomarkers in Head and Neck Cancer: Advancing Non-Invasive Detection and Tailored Management

Background: Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most common malignancy worldwide, with approximately 600.000 new cases diagnosed annually. Despite improvements in multimodal therapy, survival rates remain unsatisfactory due to delayed diagnosis, lack of population screening and heterogeneous disease biology. In recent years, liquid biopsy has emerged as a promising, minimally invasive approach for tumor characterization and disease monitoring, with potential applications in early detection, prognosis, and treatment guidance. Methods: A comprehensive narrative review was performed through PubMed, Scopus and Embase databases to identify studies investigating circulating biomarkers in HNSCC. Eligible articles published in English up to 2025 were analyzed, focusing on diagnostic accuracy, prognostic value and predictive relevance of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cell-free RNA (cfRNA), microRNAs (miRNAs), extracellular vesicles (EVs) and viral nucleic acids. Results: Current evidence shows that ctDNA and viral ctDNA are the most clinically mature biomarkers, demonstrating high sensitivity for minimal residual disease (MRD) detection and the ability to anticipate recurrence months before imaging. In HPV-positive disease, circulating HPV DNA achieves near-perfect specificity and outperforms post-treatment PET-CT for early relapse identification. In HPV-negative tumors, TP53 mutations and methylation-based signatures show emerging diagnostic and prognostic value. CTCs, miRNAs, cfRNA, and EVs provide complementary insights into tumor biology, although clinical validation remains more limited. Advances in ddPCR and next-generation sequencing (NGS) have markedly improved detection of low-frequency variants and broadened the spectrum of actionable alterations. Nonetheless, heterogeneity among studies, lack of assay standardization and variable sensitivity thresholds remain major barriers to widespread adoption. Conclusions: Liquid biopsy represents a transformative tool in head and neck oncology, bridging precision diagnostics and personalized therapy. Its integration into clinical practice could enable earlier detection, more accurate prognostic assessment and tailored treatment adaptation. Future prospective and multi-institutional studies are warranted to validate its clinical utility and to establish standardized protocols for biomarker analysis and interpretation.